A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 3: Iodophenyltriflate Core Fragments Featuring Side Chains of Proteinogenic Amino Acids

• Published in: European journal of organic chemistry Vol. 2022; no. 17; pp. e202101278 - n/a
• Main Authors: Trobe, Melanie, Vareka, Martin, Schreiner, Till, Dobrounig, Patrick, Doler, Carina, Holzinger, Ella B., Steinegger, Andreas, Breinbauer, Rolf
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 06.05.2022; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Amino acids; Assembly; Benzene; Chains; Chemistry; Chemistry, Organic; Cross coupling; Fragments; Inhibitors; Peptide mimetics; Physical Sciences; Proteins; Protein–protein interactions; Science & Technology; Suzuki coupling; Synthesis; Triflate; DESIGN; Triflate; RECOGNITION; BUILDING-BLOCKS; Protein-protein interactions; DISCOVERY; Suzuki coupling; CROSS-COUPLING REACTIONS; Inhibitors; Peptide mimetics; PEPTIDES; INTERFACES; BINDING; DERIVATIVES
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202101278

Teraryl‐based α‐helix mimetics have proven to be useful compounds for the inhibition of protein‐protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl‐based α‐helix mimetics using a benzene core unit featuring two leaving groups of differentiated reactivity in the Pd‐catalyzed cross‐coupling used for teraryl assembly. In previous publications we have introduced the methodology of 4‐iodophenyltriflates decorated with the side chains of some of the proteinogenic amino acids. We herein report the core fragments corresponding to the previously missing amino acids Arg, Asn, Asp, Met, Trp and Tyr. Therefore, our set now encompasses all relevant amino acid analogues with the exception of His. In order to be compatible with the triflate moiety, some of the nucleophilic side chains had to be provided in a protected form to serve as stable building blocks. Additionally, cross‐coupling procedures for the assembly of teraryls were investigated. A series of iodophenyltriflate compounds decorated with the side chains of the proteinogenic amino acids Arg, Asn, Asp, Met, Trp and Tyr is reported. These fragments the set of building blocks for the modular assembly of teraryl‐based alpha‐helix mimetics through sequential Pd cross‐coupling.